The purpose of this project is to investigate the toxicokinetics of pesticide percutaneous absorption and biotransformation using established in vitro techniques with mice and human skin as well as a novel isolated perfused porcine skin flap (IPPSF) preparation. This model system is ideally suited to study these phenomenon because it is an isolated perfused tissue model which has an intact and viable epidermis in association with a functional microcirculation. This project will focus on studying the cutaneous biotransformation of pesticides using static and flow- through in vitro diffusion cell chambers and the IPPSF. This area has not received attention in the past. Using the IPPSF, the effects of altered epidermal bioenergetics, microcirculation and inhibition/induction on cutaneous biotransformation will be investigated. A strategy will be developed using deconvolution pharmacokinetic models for integrating the absorption profiles from the IPPSf into in vivo toxicokinetic models. In addition to studying the rate and extent of pesticide penetration and metabolism in these in vitro systems, the effect of anatomical site of application will be addressed in vivo in rats and pigs. Finally, the direct cutaneous toxicity of pesticides will be examined in the IPPSF since the skin may serve as a target organ in addition to being a portal of entry. Since the skin is the primary route of exposure to the systemic circulation for a number of toxicologically significant pesticides, a full characterization of their absorption profile and pattern of cutaneous biotransformation is essential before a rational strategy for risk- assessment can be formulated.